Understanding Normal and Malignant Human Hematopoiesis Using Next-Generation Humanized Mice

Abstract

Rodent models for human diseases contribute significantly to understanding human physiology and pathophysiology. However, given the accelerating pace of drug development, there is a crucial need for in vivo preclinical models of human biology and pathology. The humanized mouse is one tool to bridge the gap between traditional animal models and the clinic. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased human immune/hematopoietic cells has made in vivo functional characterization possible. As a patient-derived xenograft (PDX) model, humanized mice functionally correlate putative mechanisms with in vivo behavior and help to reveal pathogenic mechanisms. Combined with single-cell genomics, humanized mice can facilitate functional precision medicine such as risk stratification and individually optimized therapeutic approaches.

Keywords: human hematopoiesis; human immunity; humanized mouse; leukemia; xenograft.

Figure 1. In vivo analysis of heterogenous cellular interactions in hematologic and solid tumors in Humanized mice

A. Hematologic tumors: Intravenous injection of human leukemia-initiating stem cells into immune-compromised mice results in engraftment of human leukemic cells in the bone marrow (BM). By co-injecting hematopoietic stem cells or pre-leukemic stem cells as well as leukemia-initiating stem cells, normal hematopoietic and immune systems can also be reconstituted. Currently, by using transgenic or knock-in approaches, humanized BM microenvironments have been created. Interactions between the BM niche, immune cells, and leukemia cells awaits further study with the improved models of humanized mice. B. Solid tumors: Tumor cells are prepared in three distinct ways for making xenografts, i)smaller pieces for renal/subcutaneous inoculation, ii) single cell suspensions for intravenous/subcutaneous injection, or iii) organoid formation for renal/subcutaneous inoculation. Interactions between malignant cells, cancer-associated fibroblasts (CAFs), and immune cells (either tumor infiltrating lymphocytes (TILs) or myeloid derived suppressor cells (MDSCs)) awaits more study with further development of humanized mice.